Neurochemical research
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Neurochemical research · May 2012
Protective effects of mGluR5 positive modulators against traumatic neuronal injury through PKC-dependent activation of MEK/ERK pathway.
Several previous studies utilizing selective pharmacological antagonists have demonstrated that type 5 metabotropic glutamate receptors (mGluR5) are potential therapeutic targets for the treatment of numerous disorders of the central nervous system, but the role of mGluR5 activation in traumatic brain injury (TBI) is not fully understood. Here in an in vitro TBI model, the mGluR5 agonist (RS)-2-chloro-5- hydroxyphenylglycine (CHPG) and the positive allosteric modulators 3-cyano-N-(1,3- diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) were used to investigate the neuroprotective potency of mGluR5 activation. Data showed that CHPG and CDPPB suppressed the increase of LDH release and caspase-3 activation induced by traumatic neuronal injury in a dose-dependent manner, and the salutary effects were also present when these compounds were added 1 h after injury. ⋯ With the pretreatment of chelerythrine chloride, a PKC inhibitor, the surpressing effects of CHPG and CDPPB on traumatic injury-evoked LDH release and caspase-3 activation were blocked. All of these findings extended the protective role of mGluR5 activation in an in vitro model of TBI and suggested that these protective effects might be mediated by the PKC-dependent activation of MEK/ERK pathway. These results may have important implications for the development of mGluR5 modulators to treat TBI.